The present invention relates to a new nucleic acid derivative, and more particularly to a 3xe2x80x2-substituted nucleoside derivative or a pharmaceutically acceptable salt thereof, which has excellent antitumor activities and is useful as a medicine such as an antitumor agent, and use of such a compound for a medicine.
Pyrimidine compounds such as 5-fluorouracil, tegafur, UFT, doxifluridine, carmofur, cytarabine and enocitabine have heretofore been known as antitumor agents which are nucleic acid antimetabolites.
On the other hand, 1-(2-O-(tert-butyldimethylsilyl)-3-C-ethynyl-xcex2-D-ribofuranosyl)thymine has been known as a pyrimidine or purine nucleoside having an alkynyl group at a 3-position of a sugar moiety from Tetrahedron, 47, 1727-1736 (1991). There is however no description as to the medicinal utility of this compound, in particular, antitumor action. 1-(3-C-Ethynyl-xcex2-D-xylofuranosyl)thymine and 1-(2-O-(tert-butyldimethylsilyl)-3-C-ethynyl-xcex2-D-xylofuranosyl)thymine are also described ibid. The sugar moieties of these two compounds are both composed of xylose and differ in the configuration at a 3-position from the ribose in the compounds according to the present invention. Besides, the literature does not describe anything about antitumor action. compounds having an alkyl group at a 3-position of a sugar moiety are described in Japanese Patent Publication Nos. 11908/1970 and 4376/1971. However, their antitumor effects are extremely little, and they are hence of no utility value as anticancer agents under circumstances.
Accordingly, it is an object of the present invention to provide a new nucleic acid derivative which has excellent antitumor activities and is useful as a medicine, and a medicine comprising such a compound.
In view of the foregoing circumstances, the present inventor has carried out an extensive investigation. As a result, it has been found that a nucleic acid derivative at a 3-position of the sugar moiety of which a substituent has been introduced has excellent antitumor activities and is useful as an antitumor agent, thus leading to completion of the present invention.
The present invention provides a 3xe2x80x2-substituted nucleoside derivative represented by the following general formula (1): 
wherein B means a nucleic acid base which may have a substituent, Z represents a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the general formula (2): 
in which Ra, Rb and Rc may be the same or different from one another and individually represent a lower alkyl group or a phenyl group, or an oxiranyl group which may be substituted by at least one lower alkyl group, R1 and R2 individually represent a hydrogen atom or an ester-forming residue capable of easily leaving in a living body, and R3 is a hydrogen atom, a mono- or polyphosphoric acid residue, or an ester-forming residue capable of easily leaving in a living body, with the proviso that the sugar moiety is ribose, or a pharmaceutically acceptable salt thereof.
The compound of the present invention represented by the general formula (1) has excellent antitumor activities and is useful as a medicine such as a remedy for various tumors.
Accordingly, the present invention also provides a medicinal composition comprising the compound of the general formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
The present invention further provides a medicine, in particular, an antitumor agent, comprising the compound of the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention further provides use of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof for a medicine.
The present invention still further provides a method of treating or preventing a cancer of a mammal, which comprises administering an effective amount of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof to the mammal.
The present invention yet still further provides a process for the preparation of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof.
Examples of the nucleic acid residue represented by B in the general formula (1) include pyrimidine bases such as cytosine, thymine and uracil, and purine bases such as adenine and guanine.
Examples of the substituent, by which the nucleic acid base may be substituted, include halogen atoms, lower alkyl groups, acyl groups such as aliphatic acyl groups or aromatic acyl groups, and substituted oxycarbonyl groups such as lower alkoxycarbonyl groups, lower alkenyloxycarbonyl groups or aralkyloxycarbonyl groups.
Examples of the halogen atoms include fluorine, chlorine, bromine and iodine atoms.
Examples of the lower alkyl groups include linear or branched alkyl groups having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl groups.
Examples of the aliphatic acyl groups include linear or branched acyl groups having 1-6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and hexanoyl groups. Examples of the aromatic acyl groups include benzoyl, xcex1-naphthoyl and xcex2-naphthoyl. These groups may also have a lower alkyl group, lower alkoxy group, halogen atom, nitro group or the like as a substituent.
As examples of the lower alkyl group and halogen atom, may be mentioned the same groups and atoms as those mentioned above.
Examples of the lower alkoxy group include linear or branched alkoxy groups having 1-6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.
Examples of the lower alkoxycarbonyl groups include linear or branched alkoxycarbonyl groups having 2-7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups.
Examples of the lower alkenyloxycarbonyl groups include linear or branched alkenyloxycarbonyl groups having 3-7 carbon atoms, such as vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, 1-butenyloxycarbonyl and 2-butenyloxycarbonyl groups.
Examples of the aralkyloxycarbonyl groups include aralkyloxycarbonyl groups having 8-12 carbon atoms, such as benzyloxycarbonyl, phenethyloxycarbonyl, xcex1-naphthylmethyloxycarbonyl and xcex2-naphthylmethyloxycarbonyl groups. These groups may have a lower alkyl group, lower alkoxy group, halogen atom, nitro group or the like as a substituent.
Examples of the lower alkynyl group represented by Z include alkynyl groups having 2-6 carbon atoms, such as ethynyl, propynyl (1-propynyl, 2-propynyl), butynyl (1-butynyl, 2-butynyl, etc.), pentynyl (1-pentynyl, etc.) and hexynyl (1-hexynyl, etc.) groups, while examples of the lower alkenyl group include alkenyl groups having 2-6 carbon atoms, such as ethenyl, propenyl (1-propenyl, 2-propenyl, isopropenyl), butenyl (1-butenyl, 2-butenyl, 3-butenyl, etc.), pentenyl (1-pentenyl, etc.) and hexenyl (1-hexenyl, etc.) groups. Examples of the oxiranyl group having at least one lower alkyl group include oxiranyl groups substituted by one or two lower alkyl groups, such as 3-methyloxiranyl, 3-ethyloxiranyl, 3-propyloxiranyl, 3-isopropyloxiranyl, 3-butyloxiranyl, 3-tert-butyloxiranyl, 3,3-dimethyloxiranyl and 3,3-diethyloxiranyl groups.
Examples of the group represented by the general formula (2) include silyl groups substituted by three linear or branched alkyl groups having 1-6 carbon atoms, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tri-tert-butylsilyl, trihexylsilyl, dimethylethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, diisopropylmethylsilyl, di-tert-butylmethylsilyl and tert-butyldimethylsilyl groups, and diphenylmethylsilyl, dimethylphenylsilyl, tert-butyldiphenylsilyl and triphenylsilyl groups.
The ester-forming residues capable of easily leaving in a living body, which are represented by R1, R2 and R3, mean nontoxic ester residues which easily cleave in the blood and tissue of mammals including the human to release their corresponding hydroxyl compounds (namely, compounds in which R1, R2 and/or R3 turns to a hydrogen atom). No limitation is imposed on the ester-forming residue so far as it is generally well-known, protects the hydroxyl groups of the nucleoside and forms an ester. Examples thereof include acyl groups such as aliphatic acyl groups which may have a substituent and aromatic acyl groups which may have a substituent, lower alkylcarbamoyl groups, and amino acid residues.
Examples of the aliphatic or aromatic acyl groups which may have a substituent include lower alkanoyl groups, arylcarbonyl groups, heterocyclic carbonyl groups, aryloxycarbonyl groups, lower alkoxycarbonyl groups and acyloxyacyl groups.
Examples of the lower alkanoyl groups include alkanoyl groups which may have a halogen atom, lower alkoxy group or the like as at least one substituent and have 1-6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl and ethoxyacetyl groups.
Example of the arylcarbonyl groups include benzoyl and naphthylcarbonyl groups which may have a lower alkyl group, lower alkoxy group, halogen atom, carboxyl group, nitro group, cyano group and the like as at least one substituent, such as benzoyl, xcex1-naphthylcarbonyl, xcex2-naphthylcarbonyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2,4-dimethylbenzoyl, 4-ethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2,4-dimethoxybenzoyl, 4-ethoxybenzoyl, 2-methoxy-4-ethoxybenzoyl, 4-propoxybenzoyl., 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl., 2,3-dichlorobenzoyl, 2-bromobenzoyl, 4-fluorobenzoyl, 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxybenzoyl, 2-cyanobenzoyl, 4-cyanobenzoyl, 2-nitrobenzoyl, 4-nitrobenzoyl and 2,4-dinitrobenzoyl groups.
Examples of the heterocyclic carbonyl groups include 2-furanylcarbonyl, 4-thiazolylcarbonyl, 2-quinolylcarbonyl, 2-pyrazinylcarbonyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl and 4-pyridylcarbonyl groups.
Examples of the aryloxycarbonyl groups include phenoxycarbonyl, xcex1-naphthyloxycarbonyl, xcex2-naphthyloxycarbonyl, 2-methylphenoxycarbonyl, 3-methylphenoxycarbonyl, 4-methylphenoxycarbonyl, 2,4-dimethylphenoxycarbonyl, 4-ethylphenoxycarbonyl, 2-methoxyphenoxycarbonyl, 3-methoxyphenoxycarbonyl, 4-methoxyphenoxycarbonyl, 2,4-dimethoxyphenoxycarbonyl, 4-ethoxyphenoxycarboxy, 2-methoxy-4-ethoxyphenoxycarbonyl, 2-chlorophenoxycarbonyl, 3-chlorophenoxycarbonyl, 4-chlorophenoxycarbonyl, 2,3-dichlorophenoxycarbonyl, 2-bromophenoxycarbonyl, 4-fluorophenoxycarbonyl, xcex2-methyl-xcex1-naphthyloxycarbonyl, and xcex2-chloro-xcex1-naphthyloxycarbonyl groups.
Examples of the lower alkoxycarbonyl groups include alkoxycarbonyl groups having 2-6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and pentyloxycarbonyl groups.
Examples of the acyloxyacyl groups include acetyloxyacetyl, propionyloxyacetyl and xcex1-(acetyloxy)propionyl, xcex2-(propionyloxy)propionyl groups.
Examples of the lower alkylcarbamoyl groups include carbamoyl groups mono- or disubstituted by lower alkyl groups having 1-6 carbon atoms, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, penthylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl groups.
The amino acid residues mean groups which are formed by removing a hydroxyl group from a carboxyl group of an amino acid and may be derived from both natural and synthetic amino acids. Examples of such amino acids include glycine, alanine, xcex2-alanine, valine and isoleucine. However, any amino acid residues may be included so far as they are amino acid residues described in Japanese Patent Application Laid-Open No. 104093/1989.
As other ester-forming residues, any of general ester-forming residues described in, for examples, THEODORA W. GREENE, xe2x80x9cPROTECTIVE GROUPS IN ORGANIC SYNTHESIS Second Editionxe2x80x9d, JOHN WILEY and SONS, INC. (1991);  less than Shin Jikken Kagaku Koza 4 (New Experimental Chemistry Course 4) greater than  edited by The Chemical Society of Japan, xe2x80x9cSynthesis and Reaction of Organic Compounds (V)xe2x80x9d Chapter 11, pp. 2495, Maruzen (198:3); and Japanese Patent Application Laid-Open Nos. 106593/1986, 149696/1987 and 153696/1989 and conventionally used as ester-forming residues may be mentioned.
Examples of the mono- or polyphosphoric acid residue represented by R3 include monophosphate, diphosphate and triphosphate groups and hydroxyl group-protected radicals thereof. Examples of protecting groups include lower alkyl groups which may be substituted by a halogen atom or a cyano group, a benzyl group which may have a substituent, and a phenyl group which may have a substituent. Further, this residue may be a 3xe2x80x2,5-cyclic phosphate group which forms a cyclic structure with the nucleic acid base.
Preferable examples of B include cytosine, thymine, uracil, adenine, guanine, 5-fluorocytosine, 5-fluorouracil, N6-benzoyladenine, N2-acetylguanine and 2-chloroadenine. More preferable examples thereof include cytosine, uracil, adenine, 5-fluorocytosine and 5-fluorouracil.
Preferable examples of Z include lower alkynyl or lower alkenyl groups which may be substituted by a group represented by the general formula (2). More preferable examples thereof include ethynyl, propynyl, butynyl, ethenyl, trimethylsilylethynyl, triethylsilylethynyl, triisopropylsilylethynyl and triphenylsilylethynyl groups. Particularly preferable examples thereof include ethynyl and trimethylsilylethynyl groups.
A preferable example of R1 and R2 includes a hydrogen atom.
Preferable examples of R3 include a hydrogen atom and mono- and polyphosphoric acid residues. More preferable examples thereof include a hydrogen atom and a diphosphate group.
Preferable examples of the ester-forming residues capable of easily leaving in a living body represented by R1, R2, R3 include acyl groups. More preferable examples thereof include acetyl and benzoyl groups.
The preferable compounds according to the present invention are 3xe2x80x2-substituted nucleoside derivatives in which B in the general formula (1) is cytosine, thymine, uracil, adenine, guanine, 5-fluorocytosine, 5-fluorouracil, N6-benzoyladenine, N2-acetylguanine or 2-chloroadenine, Z is a lower alkynyl or lower alkenyl group which may be substituted by a group represented by the general formula (2), R1 and R2 are hydrogen atoms, and R3 is a hydrogen atom or a mono- or polyphosphoric acid residue.
More preferable compounds are 3xe2x80x2-substituted nucleoside derivatives in which B in the general formula (1) is cytosine, uracil, adenine, 5-fluorocytosine or 5-fluorouracil, Z is an ethynyl, propynyl, butynyl, ethenyl, trimethylsilylethynyl, triethylsilylethynyl, triisopropylsilylethynyl or triphenylsilylethynyl group, R1 and R2 are hydrogen atoms, and R3 is a hydrogen atom or a diphosphate group.
Particularly preferable compounds are 3xe2x80x2-substituted nucleoside derivatives in which B in the general formula (1) is cytosine or uracil, Z is an ethynyl or trimethylsilylethynyl group, and R1, R2 and R3 are hydrogen atoms.
The compounds according to the present invention also include those being in the form of a salt. No particular limitation is imposed on such salts so far as they are pharmaceutically acceptable salts. For example, in the case where R3 is a hydrogen atom, acid-added salts, such as inorganic acid salts such as hydrochlorates, hydrobromates and sulfates; and organic acid salts such as organic sulfonates such as methanesulfonates and benzenesulfonates, and aliphatic carboxylic acid salts such as acetates, propionates and trifluoroacetates may be exemplified. In the case where R3 is a mono- or polyphosphoric acid residue, alkali metal salts such as sodium, potassium and lithium salts, alkaline earth metal salts such as calcium salts, and ammonium salts may be exemplified. The compounds according to the present invention further include hydrates thereof.
The compounds according to the present invention represented by the general formula (1) can be prepared in accordance with, for example, the following reaction scheme 1 or 2. 
wherein B and Z have the same meaning as defined above, R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 denote individually a protecting group for a hydroxyl group, Y means a silyl protecting group, and R4 stands for a hydrogen atom or a mono- or polyphosphoric acid residue.
No limitation is imposed on the protecting groups for the hydroxyl groups represented by R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 so far as they may be used as usual protecting groups for nucleosides. Examples thereof include acyl groups such as aliphatic acyl groups which may have a substituent and aromatic acyl groups which may have a substituent, lower alkoxycarbonyl groups, lower alkylcarbamoyl groups, lower alkyl groups, arylalkyl groups, silyl protecting groups, and amino acid residues.
As the acyl groups such as aliphatic acyl groups or aromatic acyl groups, the lower alkoxycarbonyl groups, the lower alkylcarbamoyl groups and the amino acid residues, there may be used those described above. As the lower alkyl groups, those described above may be used, while alkyl groups having a halogen atom, lower alkoxy group or the like as a substituent, such as chloromethyl, methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl groups, may be included.
Examples of the arylalkyl groups include benzyl, benzhydryl and trityl groups. These groups may have a lower alkyl group, lower alkoxy group, halogen atom, nitro group or the like as a substituent.
Examples of the silyl protecting groups include trimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, triisopropylsilyl and tetraisopropyldisiloxyl (TIPDS). The same may be said of the silyl protecting group represented by Y.
(Process A)
A compound represented by the general formula (3) is reacted with a silylated nucleic acid base represented by the general formula (4), thereby obtaining a compound of the present invention represented by the general formula (1-a).
The compound represented by the general formula (3) is a known compound or obtained in accordance with any known method. More specifically, the compound can be prepared in accordance with Reaction Scheme 3 which will be described subsequently.
The silylated nucleic acid base represented by the general formula (4) is a known compound or obtained in accordance with any known method. In general, the compound can be obtained by using, for example, the method disclosed by vorbruggen et al. (Chem. Ber. 114, 1234 (1981)). More specifically, a suspension is prepared from a nucleic acid base and a silylating agent such as hexamethyldisilazane. Trimethylsilyl chloride is further added to the suspension as needed, and the mixture is heated under reflux in an argon atmosphere, thereby obtaining the intended compound.
The reaction of Process A is conducted in the presence of a Lewis acid in a nonpolar solvent.
No particular limitation is imposed on the Lewis acid. However, examples thereof include trimethylsilyl trifluoromethanesulfonate, tin tetrachloride and titanium tetrachloride. As the nonpolar solvent, any solvent may be used so far as it does not participate in the reaction. Examples thereof include chloroform, dichloromethane, dichloroethane and acetonitrile.
With respect to the proportions of the reactants in the reaction, it is preferable to use the compound of the general formula (4) and the Lewis acid in proportions of 1-10 moles, preferably 1-5 moles, and 1-10 moles, preferably 1-5 moles, respectively, per mole of the compound of the general formula (3). With respect to the reaction temperature, the Lewis acid is added at 0xc2x0 C., and the reaction is conducted at 0xc2x0-100xc2x0 C., preferably a temperature near room temperature. With respect to the reaction time, the reaction favorably progresses in 0.1-50 hours, preferably 1-24 hours.
(Process B)
In order to remove the protecting groups of the compound represented by the general formula (1-a) obtained in Process A, methods commonly used for the protecting groups used, for example, acid hydrolysis, alkaline hydrolysis, ammonium treatment and catalytic reduction may be suitably used. A compound of the present invention represented by the general formula (1-b) can be obtained by hydrolyzing the compound (1-a) with an alkali such as sodium hydroxide, potassium hydroxide or an ammonium derivative in a lower alcohol, for example, methanol in the case where the protecting groups are acyl groups by way of example, or by treating the compound (1-a) with an ammonium fluoride derivative in the case where the protecting groups are silyl groups.
With respect to the proportions of the reactants in the reaction, it is preferable to use the basic compound in a catalytic amount based on the compound represented by the general formula (1-a) in the case where the protecting groups are acyl groups. The reaction temperature is 0xc2x0-150xc2x0 C., preferably room temperature to 100xc2x0 C. With respect to the reaction time, the reaction favorably progresses in 0.1-100 hours, preferably 1-60 hours.
(Process C)
The compound represented by the general formula (1-b) obtained in Process B is phosphorylated with a phosphorylating agent in the presence of a solvent or without any solvent, thereby obtaining a compound according to the present invention represented by the general formula (1-c). Examples of the phosphorylating agent include phosphorylating agents generally used in selective phosphorylation of nucleosides at a 5xe2x80x2-position, such as phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide, anhydrous phosphoric acids such as pyrophosphoric acid and polyphosphoric acid, phosphoric acid, phosphoric monoesters such as p-nitrophenyl phosphate, tetrachloropyrophosphoric acid, and trialkylammonium pyrophosphates. Of these, phosphorus oxychloride and tributylammonium pyrophosphate are preferred. As the solvent, any solvent may be used so far as it does not participate in the reaction. Examples thereof include pyridine, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dichloromethane, chloroform, benzene, toluene, trimethyl phosphate and triethyl phosphate. The proportion of the phosphorylating agent used in the reaction is preferably 1-5 moles per mole of the compound of the general formula (1-b). The reaction temperature is xe2x88x9280xc2x0 C. to 100xc2x0 C., preferably xe2x88x922020  C. to 50xc2x0 C. With respect to the reaction time, in general, the reaction favorably progresses in about 0.5-12 hours.
Incidentally, upon the phosphorylation, 1,1xe2x80x2-carbonyldiimidazole, tetrazole, 1,2,4-triazole derivative or the like may be used as a reaction accelerator. 
wherein B and Z have the same meaning as defined above.
(Process D)
A compound represented by the general formula (5) is partially hydrolyzed in accordance with, for example, the method described in J. Org. Chem., 55, 410-412 (1990), namely, by reacting the compound (5) at 0xc2x0 C. in a mixture of trifluoroacetic acid-water, thereby conducting selective desilylation at a 5xe2x80x2-position to obtain a compound represented by the general formula (6).
The compound represented by the general formula (5) is a known compound or obtained in accordance with any known method, for example, the method described in J. Org. Chem. as described above; SYNTHESIS, 283-288 (1991); or Tetrahedron, 47, 1727-1736 (1991).
(Process E)
A substituent represented by Z is introduced in a 3-position of the compound represented by the general formula (6) to obtain a compound represented by the general formula (7). This reaction process can be performed in accordance with, for example, 1) a method in which a compound (which may be gaseous) represented by ZH or a complex of cerium chloride and ZH is reacted with the compound (6) in the presence of n-butyllithium in tetrahydrofuran, or 2) a method in which a Grignard reagent (ZMgBr) is reacted with. the compound (6) in tetrahydrofuran.
With respect to the proportions of the reactants, it is preferable to use the reaction reagent (ZH) and n-butyllithium in proportions of 1-10 moles, preferably 1-5 moles, and 1-10 moles, preferably 1-5 moles, respectively, per mole of the compound of the general formula (6). In the case where cerium chloride is used, an amount of cerium chloride to be used is preferably almost equimolar to the reaction reagent. The reaction temperature is preferably kept at xe2x88x9270xc2x0 C. or lower in the case of the method 1) in which n-butyllithium is used, or is xe2x88x9220xc2x0 to 50xc2x0 C., preferably xe2x88x9210xc2x0 C. to 10xc2x0 C. in the case of the method 2) in which the reaction is performed with the Grignard reagent. With respect to the reaction time, the reaction favorably progresses in 0.1-50 hours, preferably 1-24 hours.
(Process F)
The compound represented by the general formula (7) is hydrolyzed, for example, by reacting the compound (7) in hydrochloric acid-methanol, thereby obtaining a compound according to the present invention represented by the general formula (1-b).
The reaction temperature is 0xc2x0-100xc2x0 C., preferably a temperature near room temperature. With respect to the reaction time, the reaction favorably progresses in 1-100 hours.
Besides, the compound represented by the general formula (1-b) obtained in this process is subjected to the same reaction as in Process C of Reaction Scheme 1, whereby a compound represented by the general formula (1-c) can also be obtained.
Ester-forming residues can be introduced into the hydroxyl groups at 2xe2x80x2-, 3xe2x80x2- and 5xe2x80x2-positions of the compounds of the general formula (1-b) obtained in accordance with Reaction Schemes 1 and 2, or in the hydroxyl groups at 2xe2x80x2- and 3xe2x80x2-positions of the compound of the general formula (1-c) in accordance with any conventionally-known process, for example, the process disclosed in the above-described xe2x80x9cPROTECTIVE GROUPS IN ORGANIC SYNTHESIS Second Editionxe2x80x9d or  less than Shin Jikken Kagaku Koza 4 (New Experimental Chemistry Course 4) greater than  edited by The Chemical Society of Japan, xe2x80x9cSynthesis and Reaction of Organic Compounds (V)xe2x80x9d or the process described in Japanese Patent Application Laid-Open No. 152898/1983, 56996/1985, 106593/1986, 149696/1987 or 153696/1989, thereby deriving other compounds according to the present invention from these compounds.
The compounds according to the present invention obtained by the above reactions can be formed into salts by the conventionally known method, for example, a method in which they are reacted with any of the above-described inorganic or organic acids in a proper solvent. Examples of the solvent include water, methanol, ethanol, dichloromethane, tetrahydrofuran, ethyl acetate and hexane.
The reaction is preferably conducted at a temperature of 0xc2x0-50xc2x0 C. Besides, the compounds according to the present invention obtained by the above reactions can be formed into salts by the conventionally known method, for example, a method in which they are reacted with a strong base such as an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide, or a strong base such as sodium methoxide, potassium methoxide or sodium hydroxide in a proper solvent.
The above-described raw compound (3) can be prepared in accordance with, for example, the following reaction scheme. 
wherein Z, R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 have the same meaning as defined above.
(Process G)
A known compound represented by the general formula (8) is reacted in the same manner as in Process E in the above Reaction Scheme 2, thereby obtaining a compound represented by the general formula (9).
(Process H)
The compound represented by the general formula (9) is reacted with tetrabutylammonium fluoride in tetrahydrofuran, thereby obtaining a compound represented by the general formula (10).
With respect to the proportions of the reactants in the reaction, it is preferable to use tetrabutylammonium fluoride in a proportion of 1-10 moles, preferably 1-5 moles per mole of the compound of the general formula (9). The reaction is conducted at a temperature of 0xc2x0-100xc2x0 C., preferably a temperature near room temperature. With respect to the reaction time, the reaction favorably progresses in 0.1-2 hours, preferably 5-30 minutes.
(Process I)
The compound represented by the general formula (10) is reacted with a reactive substance, which protects a hydroxyl group, in a proper solvent, thereby obtaining a compound represented by the general formula (11).
As the solvent, any solvent may be used without any particular limitation so far as it does not participate in the reaction. In the case where a protecting group is an acyl group by way of example, it is only necessary to react an acylating agent such as an acid anhydride or acid halide in pyridine. Upon the reaction of this acylating agent, an amine such as dimethylaminopyridine or triethylamine may be added as a catalyst.
With respect to the proportions of the reactants in the reaction, it is preferable to use the reactive substance, which protects a hydroxyl group, in a proportion of 1-10 moles, preferably 1-5 moles per mole of the compound of the general formula (10). In the case where the catalyst is used, it is preferably used in a catalytic amount. The reaction is conducted at a temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably a temperature near room temperature. With respect to the reaction time, the reaction favorably progresses in 0.1-10 hours, preferably 30 minutes to 5 hours.
(Process J)
The compound represented by the general formula (11) is subjected to acid alcoholysis, thereby obtaining a compound represented by the general formula (12).
As an alcohol, it is preferable to use a lower alcohol such as methanol or ethanol. A mixed solvent of the alcohol and water may be used.
Examples of an acid compound include carboxylic acids such as formic acid and acetic acid, acid anhydrides such as acetic anhydride, acid halides such as acetyl chloride, and inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid.
With respect to the proportions of the reactants in the reaction, it is preferable to use the acid compound in a proportion of 10-50 moles, preferably 20-40 moles per mole of the compound of the general formula (11). The reaction temperature is 0xc2x0-100xc2x0 C., preferably a temperature near room temperature. With respect to the reaction time, the reaction favorably progresses in 1 minute to 10 hours, preferably 5 minutes to 5 hours.
(Process K)
The compound represented by the general formula (12) is reacted with a reactive substance, which protects a hydroxyl group, in a proper solvent, thereby obtaining a compound represented by the general formula (13).
As the solvent, any solvent may be used without any particular limitation so far as it does not participate in the reaction.
In the case where a protecting group is an acyl group by way of example, the compound (13) is obtained by reacting an acylating agent such as an acid anhydride or acid halide in pyridine. Upon the reaction of this acylating agent, an amine such as dimethylaminopyridine or triethylamine may be added as a catalyst.
With respect to the proportions of the reactants in the reaction, it is preferable to use the reactive substance, which protects a hydroxyl group, in a proportion of 1-20 moles, preferably 1-15 moles per mole of the compound of the general formula (12). In the case where the catalyst is used, it is preferably used in a catalytic amount, preferably a proportion of 1-5 moles per mole of the compound (12). The reaction temperature is 0xc2x0 C. to 200xc2x0 C., preferably room temperature to 150xc2x0 C. With respect to the reaction time, the reaction favorably progresses in 0.1-50 hours, preferably 1-30 hours.
(Process L)
The compound represented by the general formula (13) is acetylated by adding concentrated sulfuric acid to the compound (13) in acetic acid and/or acetic anhydride, thereby obtaining the compound represented by the general. formula (3).
The reaction is conducted at a temperature of 0xc2x0-100xc2x0 C. preferably a temperature near room temperature. With respect to the reaction time, the reaction favorably progresses in 0.1-24 hours, preferably 10 minutes to 5 hours.
The compounds according to the present invention obtained by the above reactions and the individual compounds can be isolated and purified by using conventionally-known separation and purification means, for example, concentration, solvent extraction, filtration, recrystallization, various chromatographies, etc.
From the compounds according to the present invention, medicinal compositions can be prepared by using suitable pharmaceutical carriers in accordance with a method known. per se in the art. As the carriers, there may be used various kinds of carriers routinely used in drugs, for example, excipients, binders, disintegrators, lubricants, colorants, flavors, smell corrigents, surfactants, etc.
No particular limitation is imposed on the dose form when the medicine or medicinal composition according to the present invention is used as a remedy for a tumor of mammals including the human. The form may be suitably selected according to the object of treatment. Specific examples of the form include parenteral preparations such as injections, suppositories, external preparations (ointments, plasters, etc.) and aerosol preparations, and oral preparations such as tablets, coated tablets, powders, granules, capsules, pills and solutions (suspensions, emulsions, etc.).
The various compositions described above are prepared in accordance with the preparation methods generally known in this field.
When the composition is prepared in the form of an injection, for example, a diluent such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol or polyoxyethylene sorbitan fatty acid ester, a pH adjustor and a buffer such as sodium citrate, sodium acetate or sodium phosphate, a stabilizer such as sodium pyrosulfite, ethylenediaminetetra-acetic acid, thioglycolic acid or thiolactic acid, and the like may be used as carriers. In this case, sodium chloride, glucose or glycerol may be contained in the medicinal preparation in an amount sufficient to prepare an isotonic solution. Besides, conventional solubilizing aids, analgesics, local anesthetics and the like may also be added. These carriers can be added to prepare subcutaneous, intramuscular and intravenous injections in accordance with a method known per se in the art.
When the composition is prepared in the form of a suppository, polyethylene glycol, cacao butter, lanolin, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, Witepsol (trade mark, product of Dynamit Nobel Co.) and the like may be used as carriers with a suitable absorbefacient added thereto.
When the composition is prepared in the form of ointments, for example, paste, cream and gel, a base, a stabilizer, a wetting agent, a preservative and the like, which are routinely used, are incorporated as needed, and the components are mixed to formulate the desired preparations in accordance with a method known per se in the art. As the base, there may be used, for example, white petrolatum, paraffin, glycerol, a cellulose derivative, polyethylene glycol, silicon or bentonite. As the preservative, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate or the like may be used.
When the plaster is prepared, it is only necessary to apply the above ointment, cream, gel or paste to a support routinely used in a method known per se in the art. As the support, a fabric or nonwoven fabric made of cotton, rayon or chemical fibers, or a film or foamed sheet of soft polyvinyl chloride, polyethylene or polyurethane is suitable.
When the composition is prepared in the form of oral solid preparations such as tablets, powder and granules, there may be used, as carriers, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid methylcellulose, glycerol, sodium alginate and gum arabic; binders such as simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, water, ethanol and potassium phosphate; disintegrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; disintegration-preventing agents such as sucrose, stearic acid, cacao butter and hydrogenated oils; absorbefacients such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerol and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silica; lubricants such as purified talc, stearic acid salts, boric acid powder and polyethylene glycol; and the like. The tablets may be provided as tablets coated with usual coatings, for example, sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film-coated tablets, double layer tablets, multilayer-coated tablets and the like.
Capsule preparations are formulated by mixing the compound according to the present invention with the various carriers exemplified above and charging the mixture into hard gelatin capsules, soft capsules and the like.
When the composition is prepared in the form of pills, there may be used, as carriers, excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc; binders such as gum arabic powder, tragacanth gum, gelatin and ethanol; disintegrators such as laminaran and agar; and the like.
Liquid preparations may be aqueous or oily suspensions, solutions, syrups or elixirs. These are prepared by using usual additives in accordance with a method known per se in the art.
The amount of the compound according to the present invention to be contained in the above preparations varies according to a preparation form, administration route, dosing plan and the like and hence cannot be absolutely said, and is suitably selected from a wide range. However, the compound may preferable be contained in a proportion of about 1-70 wt. % of the preparation.
No particular limitation is imposed on the administration method of the preparation, and an administration method such as enteral administration, oral administration, rectal administration, intraoral administration or percutaneous administration is suitably determined according to a preparation form, the age, sex and other conditions of a target to be dosed such as a patient, the diseased condition of the patient, and the like. For example, the tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally dosed, while the suppositories are intrarectally dosed. The injections are intravenously dosed by themselves or in combination with a usual fluid replacement containing glucose, amino acids and/or the like, and further intraarterially, intramuscularly, intracutaneously or subcutaneously dosed by themselves as needed. The ointments are applied to the skin, oral mucosa membrane, etc.
The dose of the compound according to the present invention is suitably selected according to an administration method, the age, sex, diseased condition and kind of a tumor of a target to be dosed such as a patient, the kind of the compound to be dosed, and other conditions. In general, it is however desirable to dose the compound in a proportion of about 1-1,000 mg for the oral preparation, about 0.1-500 mg for the injection or about 5-1,000 mg for the suppository, per preparation to be dosed. Besides, a dose per day of the medicine in the form of any of the above dose forms is preferably set on the basis of an amount ranging generally from about 0.1 to 200 mg/kg of weight/day, preferably from about 0.5 to 100 mg/kg of weight/day. These preparations according to the present invention may be dosed at once or in about 2-4 installments a day.
No particular limitation is imposed on malignant tumors which can be remedied by administering the preparation containing the compound according to the present invention. Examples thereof include head and neck cancer, esophageal carcinoma, gastric cancer, colon cancer, rectum cancer, cancer of liver, gallbladder.bile duct cancer, pancreatic cancer, pulmonary carcinoma, breast cancer, ovarian cancer, bladder cancer, prostatic cancer, testicular tumor, osteochondrosarcoma, malignant lymphoma, leukemia, cervical cancer, skin carcinoma, brain tumor and the like.